U.S. patent number 6,511,453 [Application Number 09/953,185] was granted by the patent office on 2003-01-28 for device for controlled anaesthesia, analgesia and/or sedation.
Invention is credited to Michael Georgieff.
United States Patent |
6,511,453 |
Georgieff |
January 28, 2003 |
Device for controlled anaesthesia, analgesia and/or sedation
Abstract
A device for inducing anaesthesia, analgesia and/or sedation is
described which comprises a container holding an inert
gas-containing liquid preparation, and means for the controlled
administration of the preparation to a patient.
Inventors: |
Georgieff; Michael (89081
Ulm/Ermingen, DE) |
Family
ID: |
7822782 |
Appl.
No.: |
09/953,185 |
Filed: |
September 17, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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037793 |
Mar 10, 1998 |
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Foreign Application Priority Data
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Mar 10, 1997 [DE] |
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197 09 704 |
Aug 8, 1997 [EP] |
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97 113 756 |
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Current U.S.
Class: |
604/26;
604/23 |
Current CPC
Class: |
A61P
25/00 (20180101); A61P 29/00 (20180101); A61P
23/02 (20180101); A61P 23/00 (20180101); A61K
9/0029 (20130101); A61K 33/00 (20130101); A61P
25/04 (20180101); A61P 25/20 (20180101); A61K
9/0026 (20130101); A61P 25/02 (20180101); A61P
21/02 (20180101); A61K 33/00 (20130101); A61K
31/445 (20130101); A61K 33/00 (20130101); A61K
2300/00 (20130101); A61M 2230/43 (20130101); A61M
2230/437 (20130101); A61M 16/085 (20140204); Y10S
514/816 (20130101); Y10S 514/937 (20130101); A61M
2230/43 (20130101); A61M 2230/005 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61M 037/00 () |
Field of
Search: |
;604/251,250,23,24,30,31,32,33,34,80,81,246,247,248,249 ;424/423
;514/816,937 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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DE |
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39 40 389 |
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DE |
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41 00 782 |
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DE |
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Apr 1993 |
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DE |
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44 11 533 |
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Apr 1995 |
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DE |
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44 32 378 |
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Mar 1996 |
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DE |
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0 370 637 |
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EP |
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0 357 163 |
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EP |
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0 523 315 |
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Jan 1993 |
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EP |
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WO |
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WO |
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WO 95/27438 |
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WO |
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WO 96/39197 |
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Dec 1996 |
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WO |
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WO 96/41647 |
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Dec 1996 |
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WO |
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Other References
G Kleinberger et al, Infusionstherapie, 10, pp. 108-117 (1983),
"Allegemeine Charakteristika und Fragen zur Galenik von
Fettemulsionen". .
Joyce A. Wahr, M.D., et al, Anesth Analg, 1996, 82, pp. 103-107, "A
Pilot Study of the Effects of a Perflubron Emulsion, AF 0104, on
Mixed Venour Oxygen Tension in Anesthetized Surgical Patients".
.
Gerald L. Pollack et al, J. Chem. Phys. 90 (11), Jun. 1, 1989,
"Solubility of xenon in 45 organic solvents including cycloalkanes,
acids, and alkanals: Experiment and theory". .
Der Spiegel 15/1996, pp. 196-198, "Abstieg ins Unbewu.beta.te".
.
John C. Krantz, Jr. et al., "Current Comment: A Note on the
Intarvenous Use of Anesthetic Emulsions in Animals and Man with
Special Reference to Methoxyflurane" Anesthesiology, vol. 22, pp.
491-492 (1961). .
John C. Krantz, Jr. et al., "Anesthesia LXIV: The Intravenous
Administration of Methoxyflurane (Penthrane) Emulsions in Animals
and Man" Anesth. Analg., vol. 41, pp. 257-262 (1962). .
Helmut F. Cascorbi, M.D., Ph.D., et al., "Hazards of Methoxyflurane
Emulsions in Man", "Hazards of Methoxyflurane Emulsions in Man",
Anesth. Analg. vol. 47, pp. 557-559 (1968). .
Kadhim N. Salman, Ph.D., et al, "Intravenous Administration of a
New Volatile Anesthetic, 2,2-Dichloro-1,1-Diflurooethyl Methyl
Sulfide, in Dogs and Monkeys", "Intravenous Administration of a New
Volatile Anesthetic . . . ", Am. J. Vet. Res. vol. 29, pp. 165-172
(1968). .
Pschyrembel, Klinisches Worterbuch, Walter de Gruyter, Berlin-New
York, p. 48 (1977). .
B. Biber et al., "Intravenous Infusion of halothane dissolved in
fat. Haemodynamic effects in dogs," Acta Anaesthesiol Scand, 28, p.
385-389 (1984). .
B. Lachmann et al., "Safety and efficacy of xenon in routine use of
an inhalational anaesthetic", The Lancet, vol. 335, p. 1413-1415
(Jun. 16, 1990). .
H. Luttropp et al., "Left ventricular performance and cerebral
haemodynamics during xenon anaesthesia", Anaesthesia, vol. 48, p.
1045-1049 (1993). .
F. Giunta et al., "Xenon: a review of its anaesthetic and
pharmacological properties", Applied Cardiopulmonary
Pathophysiology 00: 1-9 (1996). .
Ullmanns Encyklopadie der technischen Chemie, 4. ed., vol. 17,
Chapter Narkosemittel, Verlag Chemie, Weinheim-New York, p. 135-141
(1979). .
S. Schraag und M. Georgieff, "Intravenos Anasthesie-Aktuelle
Aspekte", Anasthesiol Intensivmed. Notfallmed. Schmertzther,
30:469-478; Georg Theieme Verlag Stuttgart-New York (1995). .
Rompp Chemie Lexikon (paperback-edition), vol. 5, Georg Thieme
Verlag, Stuttgart, "Propofol", p. 3639-3640 (1995)..
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Primary Examiner: Mendez; Manuel
Attorney, Agent or Firm: Burns, Doane, Swecker & Mathis,
L.L.P.
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION(S)
This application is a divisional of application Ser. No.
09/037,793, filed on Mar. 10, 1998, now allowed, and claims
priority to German Patent Application No. 197 09 704.9, filed Mar.
10, 1997, and European Patent Application No. 97 113 756.7, filed
Aug. 8, 1997.
Claims
What is claimed is:
1. Device for carrying out controlled anaesthesia, wherein the
intravenous supply of an infusion solution containing a lipophilic
inert gas is adjusted as a function of the inert gas concentration
in the air exhaled by a patient, comprising a container for the
infusion solution holding said solution which contains said
lipophilic inert gas and a metering means for controlling the
infusion rate.
2. Device according to claim 1 wherein a patient's experimental
data are additionally recorded, allowing a conclusion to be drawn
about the patient's depth of anaesthesia.
3. Device for controlled anaesthesia, analgesia and/or sedation,
characterized in that the device comprises a container holding a
liquid preparation which contains a lipophilic inert gas in an
amount effective as an anaesthetic, analgesic or sedative, and
means for the controlled administration of the preparation to a
patient, wherein provision is made for a storage container for a
liquid preparation which can take up an inert gas in dissolved
form, a gas container for the inert gas, and a metering means for
feeding inert gas into the mixer, in which the liquid preparation
is mixed with the inert gas.
4. Device for inducing sedation, characterized in that the device
comprises (a) a facility which provides a liquid preparation
containing a lipophilic gas in an amount active as a sedative, (b)
a means of measuring data, which records a patient's data, said
data allowing a conclusion to be drawn about the patient's
condition, and (c) a control means which controls the
administration of the emulsion from the facility to the patient as
a function of the measured data.
Description
The invention relates to a device which can be used to control the
anaesthesia, analgesia and/or sedation of a patient.
Control is understood here as meaning that a patient's condition
(anaesthesia, analgesia and/or sedation) can be changed in the
shortest possible time from the patient's actual condition to a
required or desired condition. This means e.g. that, in the case of
anaesthesia, the conditions (1) analgesia, (2) loss of
consciousness and (3) muscular relaxation are reached in the
shortest possible time and that the transition from the
anaesthetized condition to full consciousness proceeds rapidly and
without complications. Control also means that, once a condition
has been reached, it is kept stable over long periods (hours to
days). This means that, even under drastically changing
circumstances, the condition is maintained and subsequent control
can be effected without problems.
If such control is to take place reliably and without
complications, the active substance must first meet certain
requirements. For example, one feature of the active substance must
be a rapid onset of action (a few seconds). On the other hand,
however, the action must also wear off rapidly (for example 1-3
minutes; reversibility; all defunctionalization symptoms must
disappear when anaesthesia has ended). A further requirement is an
adequate (for example anaesthesiological) safety margin. The
concentration required to achieve the desired condition (for
example loss of pain sensation and loss of consciousness) should be
several times lower than that which damages the patient's vital
functions. Finally, however, the controllability is also a decisive
factor, i.e. the condition can be deepened, relieved or ended by
varying the concentration or the infusion rate. In the case of
longer-lasting operations (e.g. operations which take more than 10
seconds), an additional requirement is that the active substance
can be administered in higher concentrations over a longer period
of time without causing appreciable side effects.
Although one of the remarkable features of the intravenous
anaesthetics in current use is an immediate onset of action, they
regularly exhibit a host of disadvantages. It should be emphasized
that propofol and etomidate, in particular, have no analgesic
action and are difficult to control. Other disadvantages of these
injectable anaesthetics are side effects which are difficult to
assess (for example drop in blood pressure, bradycardia, rigidity,
allergic reactions) and in some cases serious contraindications.
Finally, total intravenous anaesthesia (TIVA) with propofol also
frequently results in protracted waking and disorientation,
especially after longer periods of anaesthesia.
Thus it is seen that the presently known intravenous active
substances do not meet the requirements.
Active substance combinations according to the state of the art do
not represent a solution to this problem. In the case of
anaesthetics in particular, it is known that combinations produce
pharmacokinetic and pharmacodynamic interactions which very
definitely cannot be adequately controlled in the maintenance of
the anaesthesia. As a consequence of the different pharmacokinetics
and pharmacodynamics of the respective active substances at a given
moment during the anaesthesia, it is not possible correctly to
adjust the concentration and/or the infusion rate. In other words,
where active substance combinations are used in an intravenous
preparation, the overall action virtually never corresponds to the
sum of the individual actions. Such combination preparations
therefore fail to meet the requirement of controllability.
There is consequently a need for a substance, to be used as a
single substance or in combination with other active substances,
which meets the requirements formulated above.
Very precise control of anaesthesia, especially the maintenance of
anaesthesia, requires that a particular concentration of active
substance in a patient's blood be unambiguously measurable at any
time. In the case of simple and easily comprehensible operating
procedures and known pharmacokinetics, limited control is possible
by means of multistage infusion regimes, for example with propofol.
However, such regimes are inflexible and are unsuitable especially
when the active substance has to be administered in a controlled
manner under changing anaesthetic and operative circumstances.
Because of the lack of flexibility of manual infusion regimes and
the highly complex mathematical models for the pharmacokinetics of
the known active substances, computer controlled infusion systems
have been developed. These computer systems are programmed with a
mathematical solution for the pharmacokinetic model of a patient in
respect of the active substance used, for example propofol. The
computer then calculates the infusion rate which is necessary to
achieve and maintain a theoretical target blood concentration. This
target value is determined and adjusted e.g. by an anaesthetist.
The computer then also controls the infusion rate at which the
active substance is administered to a patient. This type of control
is also known as target controlled infusion (TCI).
However, there is always uncertainty as regards the concentration
of the active substance because the pharmacokinetics differ from
patient to patient. It has in fact been observed that very
different target concentrations have been determined by
anaesthetists in practice. It follows from this that there is a
considerable need for a system which can adjust or control a
particular condition during anaesthesia as a function of a
patient's actual requirements during an operation. The substantial
differences in the target concentrations of the active substance in
the blood, and the appreciable variance observed in the course of
operations with different patients and the drugs additionally used,
lead to the conclusion that TCI does not yet meet the requirements
of effective control in every respect.
Systems are currently under development which make it possible to
adjust the degree of anaesthesia more precisely. These are closed
circuit systems in which the administration of the injectable
anaesthetic is controlled as a function of the depth of anaesthesia
which is actually measured (so-called closed loop anaesthesia
systems (CLAN)). However, these systems require a considerable
expenditure on equipment in order precisely to determine the action
of the anaesthetic, i.e. the depth of the anaesthesia, in a
patient.
In summary, there is therefore not only a need for a substance with
an anaesthetic, analgesic and sedative action which meets all the
requirements for use in a true control system (TCI or CLAN), as
previously discussed, but also a need for simpler systems which can
also function without complex computer programs and/or expensive
measuring instruments (as well as evaluation programs) and which,
in contrast to the known systems, reflect the true condition (for
example true concentration in the blood).
The object of the invention consists in providing a device (or
facility) which makes it possible to ensure controlled anaesthesia,
analgesia and/or sedation.
This object is achieved by means of a device which is characterized
in that it comprises a container holding a liquid preparation which
contains a lipophilic inert gas in an amount effective as an
anaesthetic, analgesic or sedative, and means for the controlled
administration of the preparation to the patient. The purpose of
this device is to administer an inert gas-containing preparation to
a patient intravenously or arterially in a time controlled manner.
"In a time controlled manner" means here that the condition
required for example in an operative procedure (anaesthesia,
analgesia and/or sedation) can always be precisely controlled over
a given period of time, for example 2 minutes or even 1 to 2 hours
or more (up to days). This is achieved for example by aiming for a
particular endtidal xenon concentration, which corresponds to the
concentration in the blood. In the very simplest case, the
container holding the liquid preparation is a syringe. The means of
controlled administration is then the syringe plunger, to which a
pressure is applied, for example with the assistance of a so-called
perfuser, said pressure affording a controlled administration of
the preparation (e.g. continuous intravenous administration of a
volume of 20 ml over 30 sec). Such a device makes it possible to
ensure the maintenance of anaesthesia over shorter periods of time
(10 sec to about 60 min). The depth of anaesthesia, the analgesia,
the sedation and/or the muscular relaxation is precisely adjusted
for example via the endtidal xenon concentration. As the
pharmacokinetics of the active substance are very much simpler than
in the case of propofol, graded infusion regimes are not
necessary.
Another embodiment comprises an infusion bag filled with the liquid
preparation, a tube for connection to the patient, and a simple
regulator for controlling the administration. More complex
embodiments comprise electronic control facilities and pumps, for
example infusion pumps.
The required adjustments for the infusion of the liquid preparation
containing an inert gas can be determined inter alia by simulating
the course of an operation on a patient beforehand, for example.
This means that the infusion rate/concentration appropriate for a
particular condition (anaesthesia/analgesia/sedation) is determined
on a patient beforehand. Such a determination can be carried out
without problems immediately before the actual operation.
The invention is partly based on the surprising discovery that a
condition of anaesthesia, analgesia or sedation can easily be
controlled with a liquid preparation containing an inert gas (Kr,
Ar, Xe). Xenon has proved particularly effective in this
context.
Xenon is a colourless, odourless and tasteless monoatomic inert gas
of atomic number 54. Xenon is five times denser than air. Naturally
occurring xenon also contains isotopes, for example the isotopes
124, 126, 128, 129, 130, 131, 132, 134 and 136. Synthetic isotopes,
like xenon 114, xenon 133 and xenon 142, are known as well. These
isotopes disintegrate with half-lives of between 1.2 seconds and
about 40 days. The present invention does not address radioactive
xenon isotopes.
Liquid preparations in terms of the present invention are generally
preparations which, by virtue of a certain lipophilicity, can
easily take up a fat-soluble gas like the abovementioned xenon or
krypton, examples of said preparations being emulsions.
To achieve a subanaesthetic action, the xenon load in the medicinal
preparation need only be about 0.2 to 0.3 ml of xenon per ml of
emulsion. This means that an analgesic and/or sedative action is
assured for preparations with a xenon content of at least 0.2 ml/ml
emulsion. An anti-inflammatory action is already observed at 0.1
ml/ml emulsion. It has been found that, with continuous infusion
over 30 sec, 20 ml of an emulsion containing 0.3 ml of Xe per ml of
emulsion produce a subanaesthetic condition in a patient weighing
about 85 kg. When working with a highly laden perfluorocarbon
emulsion containing 2 to 4 ml of xenon per ml of emulsion, for
example, 20 ml of this emulsion are infused over 30 sec, for
example, in order to induce anaesthesia. An infusion rate of at
least 7.5 ml/min is sufficient to maintain the anaesthesia. A total
of 470 ml of emulsion would thus be used for a 1-hour operation.
With a xenon content of 3 ml of xenon per ml of emulsion, this
corresponds to a xenon volume of 1410 ml, i.e. a fraction of the
xenon consumed in inhalation anaesthesia (based on a body weight of
85 kg, this would be a consumption of 16.6 ml per kg in one
hour).
It is furthermore possible, and under certain circumstances also
advantageous, to include another pharmacologically active agent in
the preparation in addition to the inert gas. This can be an
intravenous sedative or anaesthetic, for example. Depending on
whether this agent is water-soluble or fat-soluble, it is then
present in the aqueous phase or the lipid phase together with the
xenon. 2,6-Diisopropylphenol, which is an effective anaesthetic
(for example 1.5-20 mg/ml), is found to be particularly suitable
for this purpose. Etomidate in concentrations of 0.1-2 mg/ml
(Hypnomidate.RTM., an imidazole-5-carboxylic acid derivative) is
also suitable. Using dissolved xenon in addition to the other
anaesthetic makes it possible to lower the concentration of e.g.
diisopropylphenol or etomidate which is necessary for
anaesthetization. Thus, for example, 1 ml of fatty emulsion
according to the invention (containing about 0.1 g of fat per ml of
emulsion) can contain 2.5-20 mg of 2,6-diisopropylphenol, i.e. for
example 2.5, 5.0, 7.5, 10, 15 or 20 mg, in addition to the
xenon.
In very general terms, the substance with an anaesthetic, analgesic
or sedative action which is present together with the xenon can be
another anaesthetic, an analgesic, a muscle relaxant or a sedative.
Examples of other suitable anaesthetics are barbiturates (barbital,
phenobarbital, pentobarbital, secobarbital, hexobarbital and
thiopental, inter alia) in general, and opioids. Known analgesics
are, inter alia, compounds of the morphine type, e.g.
hydromorphone, oxymorphone, codeine, hydrocodone, thebacon,
thebaine and heroin. It is also possible to use synthetic
derivatives of morphine, e.g. pethidine, levomethadone,
dextromoramide, pentazocine, fentanyl and alfentanil. It is also
possible to use less potent analgesics such as anthranilic acid
derivatives (flufenamic acid, mefenamic acid), acrylic acid
derivatives (diclofenac, tolmetin, zomepirac), arylpropionic acid
derivatives (ibuprofen, naproxen, phenoprofen, ketoprofen) and
indoleacetic or indenacetic acid derivatives (indometacin,
sulindac). The muscle relaxants used can be central muscle
relaxants, for example baclofen, carisoprodol, chlordiazepoxide,
chlormezanone, chloroxazone, dantrolene, diazepam, phenyramidol,
meprobamate, phenprobamate and orphenadrine. Sedatives which can be
used according to the invention are, inter alia, benzodiazepine
derivatives such as triazolam, lormetazeban, clotiazepam,
flurazepam, nitrazepam and flunitrazepam.
Liguids which can take up lipophilic inert gases are e.g. blood
substitutes, including perfluorocarbon emulsions (e.g.
Perflubron).
It is generally known that a large number of gases have a high
solubility in perfluorocarbon compounds. A perfluorocarbon emulsion
consists for example of up to 90% (weight/volume) of perflubron
(C.sub.8 F.sub.17) Emulsifiers, for example phospholipids from
chicken egg yolk, are additionally required. These emulsions which
can be loaded according to the invention with xenon have been
reported for example by J. A. Wahr et al. in Anesth. Analg. 1996,
82, 103-7.
Suitable fluorocarbon emulsions preferably comprise 20% w/v to 125%
w/v of a highly fluorinated hydrocarbon compound, for example
polyfluorinated bisalkylethenes, cyclic fluorocarbon compounds like
fluorodecalin or perfluorodecalin, fluorinated adamantane, or
perfluorinated amines like fluorinated tripropylamine and
fluorinated tributylamine. It is also possible to use
monobrominated perfluorocarbons, for example
1-bromoheptadecafluorooctane (C.sub.8 F.sub.17 Br),
1-bromopentadecafluoroheptane (C.sub.7 F.sub.15 Br) and
1-bromotridecafluorohexane (C.sub.6 F.sub.13 Br). Other compounds
can also be used, including perfluoroalkylated ethers or
polyethers, e.g. (CF.sub.3).sub.2 CFO(CF.sub.2 CF.sub.2).sub.2
OCF(CF.sub.3).sub.2, (CF.sub.3).sub.2 CFO(CF.sub.2 CF.sub.2).sub.3
OCF.sub.2 (CF.sub.3), (CF.sub.3).sub.2 CFO(CF.sub.2 CF.sub.2).sub.2
F, (CF.sub.3).sub.2 CFO(CF.sub.2).sub.3 F and (C.sub.6
F.sub.13).sub.2 O.
Chlorinated derivatives of the abovementioned perfluorocarbons can
also be used.
The loading capacity of the abovementioned perfluorocarbon
preparation is considerable. Xenon loads of e.g. 1 to 10 ml/ml have
been achieved by the simplest means. For example, these
preparations can be loaded with inert gas simply by having the gas
passed through them.
It is also possible to use fatty emulsions containing the
lipophilic inert gas dissolved or dispersed in the lipid phase.
It has been found that xenon can be added to a fatty emulsion in
appreciable amounts. Thus, even by the simplest means, xenon can be
dissolved or dispersed in concentrations of 0.2 to 10 ml or more
per ml of fatty emulsion (concentrations relate to standard
conditions, i.e. 20.degree. C. and normal pressure). The xenon
concentration depends on a large number of factors, especially the
concentration of the fat. As a rule the preparations will be
"loaded" with xenon up to the saturation limit. However, it is also
possible for very small concentrations to be present, provided, for
example, that a pharmacological activity can still be observed on
intravenous administration. In the case of a 10% fatty emulsion, it
is easily possible to reach xenon concentrations of 0.3 to 2 ml of
xenon per ml of fatty emulsion. It is of course also possible to
reach higher values, e.g. 3, 4, 5, 6 or 7 ml of xenon per ml of
fatty emulsion. These fatty emulsions are sufficiently stable, at
least in gas-tight containers, for the xenon not to be released as
a gas over conventional storage periods.
The lipid phase of the preparation, which takes up the gas, i.e.
which can dissolve and/or disperse the. gas, is formed mainly of
so-called fats, said fats being essentially esters of long-chain
and medium-chain fatty acids. Such fatty acids, saturated or
unsaturated, contain 8 to 20 carbon atoms. However, it is also
possible to use omega-3 or omega-6 fatty acids, which can contain
up to 30 carbon atoms. Suitable esterified fatty acids are
especially plant oils, e.g. cottonseed oil, soya bean oil and
thistle oil, fish oil and the like. The major constituent of these
naturally occurring oils are fatty acid triglycerides. Preparations
in the form of so-called oil-in-water emulsions are of particular
importance, the proportion of fat in the emulsion conventionally
being 5 to 30% by weight, preferably 10 to 20% by weight. As a
rule, however, an emulsifier is present together with the fat,
proven emulsifiers being soya phosphatides, gelatin or egg
phosphatide. Such emulsions can be prepared by emulsifying the
water-immiscible oil with water in the presence of the emulsifier,
which is normally a surface-active agent. Other polar solvents can
also be present with the water, examples being ethanol and glycerol
(propylene glycol, hexylene glycol, polyethylene glycol, glycol
monoethers, a water-miscible ester, etc.). The inert gas can
already have been incorporated into the lipid phase in a previous
process step. In the simplest case,. however, the prepared emulsion
is loaded with the xenon. This can take place at various
temperatures, for example at temperatures from 1.degree. C. to room
temperature. It is occasionally useful here to apply a pressure,
for example of up to 8 atmospheres or more, to the vessel
containing the emulsion.
According to the invention, it is possible to use fatty emulsions
such as those employed in intravenous feeding. These fatty
emulsions consist essentially of a suitable fatty base (soya bean
oil or sunflower seed oil) and a well-tolerated emulsifier
(phosphatides). Fatty emulsions in general use are Intralipid.RTM.,
Intrafat.RTM., Lipofundin.RTM.S and Liposyn.RTM.. More detailed
information on these fatty emulsions can be found in G. Kleinberger
and H. Pamperl, Infusionstherapie, 108-117 (1983) 3. The fatty
emulsions generally also contain additives which make the
osmolarity of the aqueous phase, surrounding the fatty phase
present in the form of liposomes, isotonic with the blood. Glycerol
and/or xylitol can be used for this purpose. Furthermore, it is
frequently useful to add an antioxidant to the fatty emulsion in
order to prevent oxidation of the unsaturated fatty acids. Vitamin
E (DL-tocopherol), in particular, is suitable for this purpose.
So-called liposomes, which can be formed from the abovementioned
triglycerides but also generally from so-called phospholipid
molecules, are particularly advantageous as the lipid phase,
especially in the case of an oil-in-water emulsion. These
phospholipid molecules generally consist of a water-soluble part,
which is formed of at least one phosphate group, and a lipid part,
which is derived from a fatty acid or fatty acid ester.
U.S. Pat. No. 5,334,381 illustrates in detail how liposomes can be
loaded with gas. In very general terms, a device is filled with the
liposomes, i.e. with an oil-in-water emulsion, and the device is
then pressurized with the gas inside. The temperature can be
reduced to as low as 1.degree. C. in this process. The gas
gradually dissolves under pressure and passes into the liposomes.
Small gas bubbles may then form when the pressure is released, but
these are now encapsulated by the liposomes. It is thus possible in
practice to keep xenon gas or other gases, for example, in a fatty
emulsion under hyperbaric conditions. Such preparations can also be
used according to the invention, provided that a separate gas phase
does not form outside the liposomes and on condition that the
desired pharmacological action takes place.
The lipids which form the liposomes can be of natural or synthetic
origin. Examples of such materials are cholesterol,
phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine,
phosphatidylglycerol, phosphatidylinositol, sphingomyelin,
glycosphingolipids, glucolipids, glycolipids, etc. The surface of
the liposomes can moreover be modified by a polymer, for example by
polyethylene glycol.
It is self-evident that the control device according to the
invention can also include the determination of other experimental
values on a patient (for example acoustically induced potentials
etc.) in order to be able to monitor the desired controlled
condition more precisely. As inert gases are only eliminated
through ventilation via the lung, however, this is the first time
that it has been possible, in the intravenous administration of the
inert gas-containing preparation, continuously to determine the
actual concentration of an intravenous drug by measurement of the
endtidal concentration of the inert gas (particularly xenon).
Therefore both the depth of anaesthesia and the depth of analgesia,
as well as the muscular relaxation, if desired, can be precisely
controlled by controlling various true arterial concentrations. The
invention thus affords real target controlled anaesthesia. No
mathematical models for the effective plasma concentration are
necessary in this case.
As elimination takes place exclusively via the lung, precise
control of the anaesthesia is even possible in patients with a
restricted organic function, for example a liver and/or kidney
dysfunction.
The invention also provides a device for controlling anaesthesia,
the intravenous supply of the inert gas-containing infusion
solution being adjusted as a function of the inert gas
concentration in the air exhaled by the patient.
The inert gas concentration in the exhaled air can be measured
particularly easily, especially in the case of xenon, with a gas
detector.
A characteristic feature of this device is that it is particularly
simple in equipment terms. It can be used especially in emergency
medicine, where facilities with a small space requirement are
particularly advantageous.
This device can also be part of a unit used for
monitoring/controlling anaesthesia with a gaseous anaesthetic.
The invention also provides a device for inducing sedation,
especially analgesia/sedation, with (a) a facility which provides
an emulsion containing a lipophilic inert gas in an amount active
as a sedative, (b) a means of measuring data, which records a
patient's data, said data allowing a conclusion to be drawn about
the patient's condition, and (c) a control means which controls the
administration of the emulsion from the facility to the patient as
a function of the measured data. A device for (monitored)
analgesia/sedation can be useful especially in the context of
intensive care and after heart operations. This device comprises a
perfuser, optionally a means of measuring the exhaled xenon, and a
pulsoximeter. It is advantageous that analgesia can be achieved at
the same time as sedation.
In summary, the device according to the invention can be used in a
variety of circumstances, especially in intensive care, endoscopy,
cystoscopy, superficial interventions and heart operations.
The invention also provides a device for controlled anaesthesia,
the concentration of the xenon in a preparation administered
intravenously to a patient being regulated as a function of the
xenon concentration in the air exhaled by an anaesthetized patient.
Such a device optionally has a mixer in which the preparation is
mixed with the xenon. This mixer can be temperature controlled
(range from 1.degree. C. to 35.degree. C.). (The preparation can
also have been loaded with xenon beforehand.) As already described
previously, the xenon dissolves substantially in this process. In
the simplest case, the mixer can consist of a vessel through which
the preparation is passed and which is partially surrounded by a
semipermeable membrane permeable to xenon. The concentration of the
xenon in the preparation is then essentially determined by the
xenon pressure on the semipermeable membrane. Other auxiliary
means, for example active or passive stirrer elements, can
additionally be considered here in order to improve the dissolution
and/or dispersion of the xenon gas. The dissolution or dispersion
of the xenon can also be improved by ultrasonic irradiation. By
simple observation of the patient, it is now possible easily to
determine, during full anaesthesia, that xenon concentration in the
exhaled air at which the anaesthesia is still adequate. If the
depth of anaesthesia is below the adequate level, the latter can be
attained by increasing the administration of xenon by means of the
preparation. The supply of xenon via the preparation can now be
controlled by the xenon load and the infusion rate (e.g. by means
of conventional infusion pumps). This procedure virtually allows
fine control of the anaesthesia, which could not be achieved
hitherto with intravenous anaesthetics.
The invention also provides a device which substantially
corresponds to the device described above except that there is no
provision for the admixing of xenon. In such a case, the
preparation is always already loaded with xenon and the anaesthesia
is controlled by adjusting the infusion rate or the concentration
of the xenon as a function of the measured expiratory xenon
concentration. The concentration of xenon in the preparation can be
reduced for example by admixing another preparation which does not
contain inert gas. Here again, simple infusion pumps (optionally
peristaltic pumps) serve the purpose according to the invention.
Provision can be made for temperature control both in this device
and in the previously described device where xenon is mixed into
the preparation.
FIG. 1 shows a syringe such as that which can be used in principle
according to the invention. In this very simple embodiment of the
invention, the syringe, which holds a xenon-containing preparation,
can be thought of as a facility providing a preparation which
contains a lipophilic inert gas in an amount effective as an
anaesthetic, analgesic or sedative.
FIG. 2 shows a device according to the invention which is a filled
infusion bag with a regulator.
FIG. 3 shows a device according to the invention which has a filled
infusion bag with a discharge tube, and a simple regulator for
controlling the administration.
FIG. 4 shows another device according to the invention.
FIG. 5 diagrammatically shows a device according to the invention
for inducing sedation (so-called closed loop arrangement).
FIG. 6 shows a device according to the invention which is part of a
device for carrying out anaesthesia with a gas, and which includes
a means of measuring the inert gas in the exhaled air.
The device according to the invention for carrying out controlled
anaesthesia is illustrated in greater detail with the aid of the
diagram in FIG. 3.
This device comprises a storage container 30 for a liquid
preparation capable of taking up an inert gas in dissolved form, a
gas container 4 for the inert gas, and a mixer 3, in which the
preparation is mixed with the inert gas. Control devices (infusion
pumps, regulator etc.), with which the intravenous administration
to the patient is controlled, are not shown.
A device according to the invention is also illustrated in greater
detail with the aid of the diagram in FIG. 4. This device can be
used for controlled anaesthesia, the xenon concentration in the air
exhaled by an anaesthetized patient being measured by analysis and
the xenon concentration in a preparation administered intravenously
to the patient being adjusted as a function of this analytical
value. The device therefore comprises an optionally
temperature-controllable storage container 1 (temperature range
1.degree. C. to 35.degree. C.) for the preparation, which is
connected via a line 5 to a mixer 3, again optionally
temperature-controllable. The xenon, which passes from a xenon
bottle 4 into the mixer 3 via the line 6, the metering unit 2 and
another line 7, is mixed with the preparation in the mixer 3, the
bulk of the xenon dissolving in the emulsion. The xenon-containing
preparation then passes via the line 8 and a venous access into a
patient to be anaesthetized. The preparation is conveyed by means
of pumps known per se (not shown). In the medical sector, so-called
peristaltic pumps are used in the simplest case here. In the device
according to the invention, such pumps can be provided for example
in the line 5 and additionally in the line 8. The means of
endexpiratoric gas sensory analysis, and the sampling means, are
not shown. Conventionally the exhaled gas is sampled at the tube
attachment or in the region of the mouth in the case of mask
respiration or mask oxygenation during the patient's inhalation and
exhalation. Methods of determining the xenon concentration in the
exhaled air are generally known (gas detectors and the like).
(Various valves capable of regulating the inflow and outflow of
solutions and gases are also not shown.)
FIG. 5 diagrammatically shows a device according to the invention
with closed loop control for inducing sedation. Here, on the one
hand, the effective xenon concentration in the blood is measured by
measuring the inert gas in the exhaled air. On the other hand,
other experimental data (for example acoustically induced
potentials) are recorded on the patient. Both experimental results
are used for controlling the perfusion pump.
The data pertaining to the xenon concentration in the exhaled air
(xenon sensor/detector 9) and the acoustically induced potentials
(recorder 10), recorded on a patient 20, are fed to the perfusion
pump 21 via the data lines 22 and 23. The experimental data are
processed (for example by means of a computer) and converted to the
required infusion rate at which the xenon-containing preparation
enters the patient via the line 8. In other words, the measured
experimental data control the perfusion pump 21, which in turn
determines the infusion rate. The device illustrated here is of
course only a diagram and an actual device comprises indicators and
regulators etc., as conventionally provided, for example in order
also to allow manual intervention in the control. The supply line
to the perfusion pump, and a storage container providing a
xenon-laden preparation, are not shown.
FIG. 6 diagrammatically shows how a device according to the
invention can be incorporated into the general control of
anaesthesia. This device comprises a storage container 1 for the
preparation, the mixer 3, a xenon bottle 4 and a metering unit 2.
The metering unit 2 is linked to a xenon detector 9, which measures
the xenon concentration in the air at the end of exhalation and
feeds an experimental value to the metering unit 2. The metering of
the xenon into the liquid preparation is then controlled by the
metering unit 2. The xenon-containing preparation then passes from
the mixer 3 through the infusion tube 8 into the patient. The
infusion rate can of course also be controlled via the xenon
concentration in the exhaled air.
A control device 40 is also provided for supplying a gaseous or
inhalation anaesthetic. This device comprises inlet and outlet
tubes 31 and 32 for supplying and withdrawing the anaesthetic gas
via the inhaling mask 35.
Experimental Section
Fatty Emulsions
The commercially available Intralipid preparations (obtainable from
Pharmacia & Upjohn GmbH, Erlangen) were used as fatty emulsions
in the following Examples. These emulsions consist essentially of
soya bean oil, 3-sn-phosphatidylcholine (from chicken egg yolk) and
glycerol. An Intralipid.RTM.10 fatty emulsion, for example, has the
following composition:
Soya bean oil 100 g (3-sn-Phosphatidyl)choline from 6 g chicken egg
yolk Glycerol 22.0 g Water for injections ad 1000 ml
Adjusted to pH 8.0 with sodium hydroxide. Energy value/1: 4600 kJ
(1100 kcal) Osmolarity: 260 mOsm/l
An Intralipid.RTM.20 fatty emulsion, for example, has the following
composition:
Soya bean oil 200 g (3-sn-Phosphatidyl)choline from 12 g chicken
egg yolk Glycerol 22.0 g Water for injections ad 1000 ml
Adjusted to pH 8.0 with sodium hydroxide. Energy value/l: 8400 kJ
(2000 kcal) Osmolarity: 270 mOsm/l
Loading of Perfluorocarbon Emulsion with Xenon
A series of perfluorocarbon emulsions were prepared or purchased
and loaded with xenon. The activity of the preparations was
verified on an animal model (rabbit). All the emulsions were used
in the same way as the Intralipid preparations described above,
i.e. the experimental animal was quickly anaesthetized by an
injection in the ear (about 1 ml).
Each of the emulsions was placed in a beaker and loaded by having
the xenon gas passed through it.
The following perfluorocarbon compounds were used:
perfluorohexyloctane (1), perfluorodecalin (2), perflubron (C.sub.8
F.sub.17) (3).
Emulsifiers, for example egg yolk lecithin (Lipoid E100 from Lipoid
GmbH, Ludwigshafen), Pluronic PE6800 and Pluronic F68, were also
used to prepare the emulsions.
It was established with all the emulsions that a perfluorocarbon
emulsion of only 40% (weight/volume, i.e. weight of perfluorocarbon
compound to volume of emulsion) could take up 1 to 4 ml of xenon
per ml of emulsion.
Experimental Animal Studies
To demonstrate that it is possible according to the invention to
control anaesthesia, in this case maintain anaesthesia, an
experiment was performed on 24 pigs aged 14 to 16 weeks and
weighing 36.4-43.6 kg. They were randomly divided into a total of 3
groups, which were anaesthetized. In all the groups the anaesthesia
was induced intravenously with a bolus injection of pentobarbitone
(8 mg/kg body weight) and buprenorphine (0.01 mg/kg body weight).
In one group (comparative group) the anaesthesia was maintained by
the intravenous administration of 2,6-diisopropylphenol (10 mg/1 ml
emulsion). For maintenance of the anaesthesia, two groups of pigs
(according to the invention), each containing four individuals,
received an intravenous infusion of 1 ml/kg/h of a 10% by weight
fatty emulsion according to the invention which had previously been
saturated with xenon (about 0.3 ml of xenon per ml of emulsion). In
group 2, 7.5 mg/kg body weight/h of 2,6-diisopropylphenol were
additionally administered with the fatty emulsion.
The pigs underwent a surgical intervention (standard intervention:
section of the left femoral artery) (identical in each group and
for each experimental animal) and the adrenaline level, heart rate,
arterial blood pressure and oxygen consumption were recorded. It
was also established how much additional pentobarbitone needed to
be administered in order to bring the analgesia and depth of
anaesthesia to the required level in each group.
TABLE Arterial Adrenaline Heart blood Pentobar- pg/ml rate pressure
VO.sub.2 bitone Group requirement [min.sup.-1 ] [mm Hg] [ml/min]
mg/kg/min Comparative 60 115 110 410 0.25 group 134 120 105 391
0.36 112 105 115 427 0.31 85 98 101 386 0.42 Group 1 38 112 112 341
0.09 21 106 100 367 0.04 16 95 104 348 0.11 30 112 118 334 0.15
Group 2 10 88 100 325 -- 23 100 85 346 -- 14 94 93 331 -- 8 104 87
354 --
The values indicated in the Table show that the xenon-containing
preparation is superior to all the currently available intravenous
anaesthetics, especially on account of the additional analgesic
potency. Thus the pigs in group 1 (10% by weight fatty emulsion
saturated with xenon) show, by comparison (cf. comparative group),
markedly less stress (adrenaline level), a lower oxygen requirement
(VO.sub.2) and a lower pentobarbitone requirement (i.e. better
anesthesia). The difference relative to intravenous anaesthetics
according to the state of the art is even more clearly apparent
when the results in group 2 (10% fatty emulsion with
2,6-diisopropylphenol and enriched with xenon) are compared with
the comparative group. This shows not only markedly reduced stress
(adrenaline level). With a markedly reduced heart rate and lower
arterial blood pressure, coupled with a lower oxygen requirement,
it was possible to dispense with the admistration of additional
amounts of pentobarbitone.
this study shows that the desired aim, in this case to maintain the
anaesthesia, can be achieved over the whole course of the
anaesthesia.
The use of perfluorocarbon preparations was studied on another
group (4 pigs of 31.4 to 39.8 kg body weight). A 40%
perfluorocarbon emulsion with a xenon content of 2.1 ml of xenon
per ml of emulsion was used on this experiment group. For induction
and intubation, the pigs received 20 ml of the emulsion
intravenously over 20 sec (corresponding to 1.34 ml xenon/kg body
weight). After incubation and respiration, xenon was continuously
infused intravenously over 30 min, the experimental animals thereby
receiving a total of 75 ml of emulsion (corresponding to 10 ml
xenon kg.sup.-1 h.sup.-1).
Arterial Adrenaline Heart rate blood pressure [pg/ml] [min.sup.-1 ]
[mm Hg] VO.sub.2 [ml/min] 8 90 101 301 6 87 96 320 10 94 98 308 5
100 106 316
The above Table indicates the experimental results for the
adrenaline level, the heart rate, the arterial blood pressure and
the oxygen consumption. The results show that, by increasing the
xenon load and infusion rates (over 5 ml/kg/h), complete
anaesthesia can be effected using only the means according to the
invention. Overall, it is even established that the oxyen
requirement (V.sub.2) is lower and the anaesthesia (adrenaline
level and heart rate) is less stressed.
* * * * *